THE EFFECTS OF REPEATED SUB-ERYTHEMAL EXPOSURES OF UVR ON HUMAN IMMUNITY

Transcription

1 THE EFFECTS OF REPEATED SUB-ERYTHEMAL EXPOSURES OF UVR ON HUMAN IMMUNITY Joanna Narbutt Department of Dermatology Medical University of Lodz, Lodz, Poland

2 Photoimmunosuppression ULTRAVIOLET RADIATION DNA damage Isomerisation of UCA trans to cis Alterations in cutaneous mediators: cytokines, PGE2, cyclooxygenases, Depletion of Langerhans cells from epidermis Generation of antigen-specific T regulatory cells and modulation of T cell response SUPPRESSION OF CONTACT HYPERSENSITIVITY RESPONSE

3 Objectives of the studies To learn the effect of repeated sub-erythemal irradiation of SSR/UVB on human immunity LCs Cytokine, PGE2 and cyclooxygenases alterations CHS response

4 Threshold of UV doses which triggers the cascade of immunological changes Question: Do photoprotection and photoadaptaion exist?

5 Whole body irradiation SSR (1,2 SED) 10 days 0.7 MED UVB (n=30) 2 days (n=34) 10 days (n=33) 30 days (n=34) Local irradiation (buttock skin) 3 MED UVB (n=30) 4 MED UVB (n=10) Photoadaptation 10 days 1.2 SED SSR + 3 MED UVB (n=30) 10 days 0.7 MED UVB + 3 MED UVB (n=30) Controls (unirradiated) n=40

6 SSR and LCs After repeated SSR exposures CD1a+ cells migrate to lower parts of the epidermis and are less dendritic CD1a+ cells number is reduced at CHS elicitation site; it correlates negatively with SSR cumulative dose (Lesiak et al., Contact dermatitis 2007)

7 CD1a+ cells in skin biopsies during the elicitation phase of CHS unirradiated, sensitized 2xSSR, sensitized 10xSSR, sensitized 30xSSR, sensitized

8 MDC1 BLOOD DENDRITIC CELLS (Epidermis and dermis) PDC No effect of UVB on their number and distribution (Narbutt et al.. Folia Histochem 2005)

9 SSR and BLOOD DENDRITIC CELLS The percentage of total BDCs was elevated in all groups by the SSR (0.3 MED daily) exposure The MDC2s showed an increase after 10 days, and a subsequent decrease after 30 days irradiation - photoadaptation (Narbutt et al., Scand J Immunol 2004)

10 SSR and cytokines mrnas Repeated sub-erythemal SSR exposures increased the expression of IL-1beta, IL-6, IL-10 and TNF-alpha mrnas in skin biopsies After 30 SSR the expression of IL-1beta, IL- 6, IL-10 mrnas showed a tendency to decrease tendency to photoadaptaion? (Narbutt et al. J Dermatol Sci 2007)

11 SSR and Cyclooxygenases UV exposure of the skin induces the expression of the COX-2 and prostaglandin PGE2 COX-2 is overexpressed in premalignant lesions and in NMSC in humans UV-induced COX-2 expression plays a major role in UVinduced PGE2 production, inflammation, edema, keratinocyte proliferation, epidermal hyperplasia, and generation of oxidative DNA damage. Chronic exposure to UV leads to up-regulation of COX-2 expression and chronic inflammation with the accumulation of DNA damage

12 SSR/COX-1 and COX-2 COX-1 Control 2 days SSR 10 days SSR 30 days SSR COX-2 Control 2 days SSR 10 days SSR 30 days SSR Number of COX-1+and COX-2+ cells increased significantly after irradiations (Narbutt et al., Exp Dermatol 2007)

13 Liczba komórek dtt+/mm p<0,05 p<0,05 Kontrola 2 dni 10 dni 30 dni DNA damage (SSR) Controls 2 d SSR 30 d SSR 10 d SSR

14 Liczba komórek dtt+/mm p<0,05 Kontrola 10 dni UVB 3 MED DNA damage (UVB) 10 DNI UVB 3 MED UVB

15 Photoadaptation 10 d UVB+3MED DNA damage (UVB and SSR) 1200 Liczba komórek dtt+/mm p=0,0001 p=0, d SSR+3MED 10 DNI UVB+3MED 10 DNI SSR+3MED 3MED

16 CHS and repeated SSR Assessment of the contact hypersensitivity reaction - used to evaluate the immune response following UV exposure Few studies Most experiments : sources emitting a higher proportion of UVB to UVA (often more than 50% UVB) compared with that found in sunlight (about 3.4% UVB and 96.6% UVA) Solar simulated radiation (SSR)

17 CHS and repeated SSR - results Irradiation with suberythemal doses of SSR suppression of CHS (Narbutt et al., Photochem Photobiol Sci 2005).

18 SSR/PAR Group 1 (n=40) Control 2 (n=33) 2 days SSR 3 (n=34) 10 days SSR 4 (n=33) 30 days SSR % subjects with PAR (p=0.03) % subiects with bisters (p=0.03) Mean time of PAR occurrence (days)

19 SSR/VISUAL ASSESSMENT OF CHS CHS Group 1 n=40 Control Group 2 n=33 2 daysssr Group 3 n=34 10 days SSR % 24.2% 35.3% Goup 4 n=33 30 daysssr 54.5% (p=0.015; R=-0.2) % 75.8% 64.7% 45.5%

20 Control 85% 10 days SSR 76% 2 days SSR 78% Cumulative dose vs. spongiosis R=-0.2; p= days SSR 57%

21 Daily exposure to a low dose of SSR over a period of 30 days can reduce the PAR and the CHS response to DPCP in human subjects, as assessed by clinical scoring and histology while no adaptation to these effects become evident

22 The results obtained indicate that repeated sub-erythemal doses of SSR do not cause clinical symptoms of inflammation but are responsible for skin immunity alterations

23 The results demonstrate the hazardous effects of sub-erythemal doses of UVR

24 Further investigations are required to measure other types of innate and acquired immune responses under low chronic UVR doses, particularly those thought to be important in the control of tumours and infectious diseases